Prenatal exposure to alcohol can produce serious detrimental effects on the developing fetus which can later result in a range of physical, neurological, and behavioral symptoms collectively termed fetal alcohol spectrum disorders (FASDs). Despite public awareness of the effects of alcohol consumption during pregnancy, the CDC reports about 7.6% of women in the U.S. drink alcohol during pregnancy making FASD one of the most prevalent developmental disorders. Thus, FASD continues to be a persistent public health problem, making understanding and treating the disorder essential. Clinical studies have shown, in addition to other symptoms, children and adults with FASD show hyper-responsiveness to stress and are particularly vulnerable to psychiatric disorders, particularly mood disorders. The neurobiology of these emotional disturbances are not well understood, but studies utilizing animal models have shown developmental exposure in rodents disrupts hypothalamic-pituitary-adrenal (HPA) axis function and its physiological response to stress. The proposed experiments utilize a rodent model of FASD - rats exposed to alcohol during the early postnatal period, which is equivalent to the third trimester in humans - to explore the neurobiology of HPA axis disruption as a consequence of developmental alcohol exposure. In rats and mice, early life exposure to alcohol induces hypothalamic -endorphin (BEP) cell death and a loss of BEP inhibitory control of the HPA axis function. Activation of microglia, the immune cells of the central nervous system, mediates the apoptotic and endocrine- disrupting effects of developmental alcohol on the HPA axis. Hypothalamic microglia contain d opioid receptors (DOR) and opioid receptors (MOR), which regulate the HPA axis and immune function. It is unknown if developmental alcohol exposure affects microglial DOR or MOR expression or activity. To explore this issue, Aim 1 will investigate the effects of developmental alcohol exposure on opioid receptor levels in microglia and its relation to BEP neuronal death. In cultured microglial cells, preliminary studies suggest that pharmacological inactivation of MORs, and, conversely, activation of DORs decrease ethanol-induced apoptosis, suggesting MORs may augment, while DORs may oppose the neurotoxic effects of developmental alcohol exposure. Thus, Aim 2 will determine the role of opioid receptors in modulating the effects of developmental alcohol exposure on microglial cell function in vivo. Furthermore, microglial DORs and MORs may mediate the detrimental effects of early life alcohol exposure on HPA axis function. Thus, Aim 3 will determine the role of opioid receptors in modulating the effects of developmental alcohol exposure on HPA axis disruption. The results from these studies will elucidate the mechanism by which developmental alcohol exposure results in HPA system disruption, which would have direct implications for understanding the neurobiology of mood disorders in patients with FASD. In addition, these studies would evaluate MORs and DORs as potential pharmacological targets for preventing or treating FASD.